Excess consumption of ethanol (alcohol) imposes serious problems for human health and has major negative economic impact. A predisposition towards alcohol overconsumption has a genetic component, and the discovery of the genes involved may lead to better control of alcohol consumption. Animal models can provide an efficient tool for discovering such genes. The long-term goal of our studies is to positionally clone genes affecting voluntary ethanol consumption by mice. Our laboratory has recently shown that a quantitative trait locus (QTL) associated with the sweet taste receptor gene, Tas1r3, influences alcohol consumption, suggesting that the taste of alcohol may be an important factor in regulation of intake. A preliminary genome scan indicates several other loci that influence intake of both ethanol and sweeteners. The aim of the current project is high-resolution genetic mapping of these loci. In Specific Aim 1, we will conduct QTL mapping using F2 hybrid and backcross generations originating from two mouse strains with high [C57BL/6ByJ (B6)] and low [129P3/J (129)] ethanol consumption. Dense genotyping and linkage analyses will detect loci responsible for the difference between the B6 and 129 mice in ethanol preference. In Specific Aim 2, these loci will be isolated using genotype-based selection of congenic strains originating from the B6 and 129 strains. In these congenic strains, the size and location of the donor chromosomal fragments will be defined, QTL positions will be determined with high resolution, and possible epistatic interactions among QTLs will be assessed. Detailed characterization of the behavioral responses to ethanol and their relationships with responses to sweeteners will help to elucidate possible mechanisms underlying QTL effects. In Specific Aim 3, based on QTL positions and possible mechanisms of action, and using the sequences of mouse and human genomes, candidate genes will be analyzed in genomic regions encompassing the QTLs. Through these three aims, we intend to isolate loci involved in ethanol preference, identify candidate genes for these loci in mice, and specify their human orthologs.